Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
Autor: | Jack H. Van der Meulen, Jennifer M. Peterson, Helen Johnston, Aditi Phadke, Jessica F. Boehler, Aurelia Defour, Vanessa E. Jahnke, Kanneboyina Nagaraju, Qing Yu, Jyoti K. Jaiswal, Kitipong Uaesoontrachoon |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
lcsh:Diseases of the musculoskeletal system Muscle Proteins Mitochondrion Sarcomere Cell Line Myoblasts Mice 03 medical and health sciences 0302 clinical medicine Loss of Function Mutation medicine Animals Myocyte Orthopedics and Sports Medicine PPAR delta Muscular dystrophy Molecular Biology Cells Cultured MyoD Protein Organelle Biogenesis biology Calpain Muscle cell differentiation Research PAX7 Transcription Factor Skeletal muscle Cell Biology medicine.disease Mitochondria Muscle Cell biology Mitochondria Mice Inbred C57BL Thiazoles 030104 developmental biology medicine.anatomical_structure Mitochondrial biogenesis biology.protein Calpain-3 deficiency Muscle membrane repair lcsh:RC925-935 030217 neurology & neurosurgery LGMD2A |
Zdroj: | Skeletal Muscle, Vol 10, Iss 1, Pp 1-17 (2020) Skeletal Muscle |
ISSN: | 2044-5040 |
Popis: | BackgroundNonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has remained elusive.MethodsCell growth, gene expression profiling, and mitochondrial content and function were analyzed using muscle and muscle cell cultures established from healthy and calpain-3-deficient mice. Calpain-3-deficient mice were also treated with PPAR-delta agonist (GW501516) to assess mitochondrial function and membrane repair. The unpairedttest was used to assess the significance of the differences observed between the two groups or treatments. ANOVAs were used to assess significance over time.ResultsWe find that calpain-3 deficiency causes mitochondrial dysfunction in the muscles and myoblasts. Calpain-3-deficient myoblasts showed increased proliferation, and their gene expression profile showed aberrant mitochondrial biogenesis. Myotube gene expression analysis further revealed altered lipid metabolism in calpain-3-deficient muscle. Mitochondrial defects were validated in vitro and in vivo. We used GW501516 to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice. This treatment improved satellite cell activity as indicated by increased MyoD and Pax7 mRNA expression. It also decreased muscle fatigability and reduced serum creatine kinase levels. The decreased mitochondrial function also impaired sarcolemmal repair in the calpain-3-deficient skeletal muscle. Improving mitochondrial activity by acute pyruvate treatment improved sarcolemmal repair.ConclusionOur results provide evidence that calpain-3 deficiency in the skeletal muscle is associated with poor mitochondrial biogenesis and function resulting in poor sarcolemmal repair. Addressing this deficit by drugs that improve mitochondrial activity offers new therapeutic avenues for LGMD2A. |
Databáze: | OpenAIRE |
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